In immunocompetent individuals, non-typhoidal Salmonella enterica serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, suppression of immunity in individuals with underlying disease can result in the development of life-threatening systemic infections. There is currently an epidemic of disseminated NTS infections in sub-Saharan Africa, which are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. Epidemiological associations suggest that while HIV infection is the most common predisposing condition for NTS bacteremia in adults, malnutrition and Plasmodium falciparum malaria are the most common underlying factors in children. The magnitude of this infectious disease problem is considerable, however the mechanisms by which malaria increases initial susceptibility to NTS infection are poorly understood. Given the high burden of malaria in children under 5 in sub-Saharan Africa, this gap in knowledge is important to address. The objective of this application is to define how alterations to the intestinal environment during malaria increase the ability of NTS to colonize the intestine after ingestion. Our central hypothesis is that malaria-induced shifts in the composition of the gut microbiota provide a favorable metabolic environment for establishment of Salmonella infection in the intestinal lumen. This hypothesis has been formulated based on our preliminary data showing that shifts in the microbiota of malaria parasite-infected mice are sufficient to increase infectivity of Salmonella enterica serotype Typhimurium (S. Typhimurium). The approach we will use to refine and test our hypothesis comprises two specific aims: (1) Identify metabolic intermediates produced by the microbiota that support increased colonization of S. Typhimurium in the intestinal lumen during malaria; and (2) Determine whether malaria parasite infection generates respiratory electron acceptors that promote NTS colonization. Our hypothesis is highly innovative, since malaria is traditionally considered a bloodstream infection, and its effects on the intestine are only beginning to be appreciated. The rationale for the proposed research is that a better understanding of alterations to the intestinal environment during malaria will provide important insights into both malaria pathogenesis and Salmonella colonization, and may ultimately point to potential intervention strategies to protect children against colonization by NTS.